Sodium nitroprusside, SNP, [Na.sub.2 Fe(CN).sub.5 NO.2H.sub.2 O] is a potent, fast acting, intravenous hypotensive agent. It is used to lower blood pressure during hypertensive and cardiac emergencies, for the clinical treatment of malignant hypertension and to lower cardiac back pressure during periods of cardiac insufficiency (Pharmacology of Antihypertensive Drugs, Ed.-A. Scriabine, Raven Press, N.Y., 1980, "Sodium Nitroprusside", V. A. W. Kreye, pg. 373-396) and for inducing "controlled hypotension" during many different types of surgery.
It acts specifically on the vascular smooth muscles, affecting their relaxation and thereby, vasodilation and lower cardiac back pressure. Its full effects are expressed in less than a minute, persist until infusion is terminated and dissipate within five to ten minutes (Tinker, J. H. & Cucchiara, R. F., Int. Anesthes. Clin. 16, 89, 1978).
Considering the wide popularity of SNP and the fact that it has been available for over half a century, surprisingly little is known about its molecular pharmacology. At the present time there is considerable evidence supporting the hypothesis that relaxation by SNP is mediated through activation of guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), (Rapport, R. M. and Murad, F., J. Cyclic Nucl. Pro. Phos. Rev. 9, 281, 1983)].
There has been controversy about the actual species involved in the activation of guanylate cyclase. Although Arnold et al (Proc. Nat'l. Acad. Sci. USA 74, 32093, 1977 and Mittal and Murad (Proc. Nat'l. Acad. Sci. USA 74, 4360, 1977) demonstrated activation of guanylate cyclase by nitric oxide and suggested that the latter moiety may be the common proximate species mediating SNP, there is no chemical evidence as to how SNP spontaneously, rapidly releases the NO moiety. Other reports (Ignarro et al., FEBS. Lett. 110, 275, 1980, and Craven et al, Biochem. Biophys. Acta 745, 310, 1983) have shown that some S-nitrosothiols, mainly S-nitrosocysteine, which was obtained from the reaction of cysteine with NO gas, activate guanylate cyclase and lower the blood pressure. The chemical and pharmacological mechanisms involved, however, are far from clear. Furthermore, their proposed mechanism which is based on the instability of S-nitrosocysteine and subsequent effects of NO formed upon its breakdown without any chemical evidence, has been recently challenged (Craven, P. S. and DeRubertis, F. R., Biochem. Biophys. Acta 745, 310, 1983).
Sodium nitroprusside (SNP) is administered under careful supervision to effect rapid short-term reductions in blood pressure. The physiological degradation of SNP and can be detected in the blood stream of patients during and after its administration. Cyanide, one product of that degradation, is normally converted by the liver to thiocyanate which is then slowly cleared by the kidneys. Cyanide, especially, and thiocyanate are both very toxic. Their toxicities limit the amounts of SNP that may be safely administered and almost completely preclude its administration to patients with impaired liver or kidney function. Because thiocyanate is a strong inhibitor of thyroxine biosynthesis, SNP is also precluded for patients with thyroid dysfunction.
Accordingly, the development and usage of hypotensive agents or anti-hypertensive drugs, which if used in place of SNP would eliminate the side effects and risks associated with the latter's metabolic degradation to cyanide and thiocyanate, would be highly desirable and provide advantages and a significant advance in the art.